α-Helices are the most common form of protein secondary structure [1], and they play critical roles in mediating a diverse array of protein-protein interactions (PPIs) that include signal transduction, transcription, apoptosis, and immune responses [2]. Molecules that can reproduce the spatial and angular projections of key side chains of α-helices are of interest as novel biochemical tools and/or new leads for drug discovery [3]. Exhibiting random coil in solution and prone to metabolic degradation, short peptides themselves, however, do not represent attractive leads [4]. Instead, several alternative strategies towards effective mimicry of the α-helix have been adopted, which include the introduction of side chain constraints into peptides, such as salt [5], lactam [6] and disulfide [7] bridges. An especially noteworthy application of this approach is manifested in the “hydrocarbon stapled” α-helices in which olefin metathesis between unnatural amino acid side chains “locks” the peptide into the desired α-helical conformation [8]. β-peptide foldamers that fold into helical structures have also been described [9]. Pre-organization not only increases binding affinity to target proteins but also improves metabolic stability [8].
Complementary to these peptidomimetic approaches, Hamilton previously pioneered a proteomimetic strategy, in which small-molecule, non-peptidic scaffolds are suitably decorated to accomplish mimicry of the spatial and angular projections of key side chains of α-helices [10]. The original α-helix mimetic scaffold described by Hamilton is the terphenyl scaffold [11], which has inspired a wide range of related frameworks, including a variety of five and six-membered heterocycles [12], derivatives of terephthalic acid [13], as well as tris-picolinamides [14] and tris-benzamides [15], and combinations thereof [16]. Until recently, synthetic α-helix mimicry focused on replication of only the hydrophobic face of the α-helix, typically the i, i+3/4 and i+7 residues. Rebek and Hamilton later introduced α-helix mimetics in which heteroatoms were incorporated into the opposite face of the scaffold to improve aqueous solubility [17]. Around 50% of the α-helices that are found in proteins are amphipathic, presenting both a hydrophobic face and a hydrophilic face [18].
It is of interest, therefore, to develop synthetic α-helix mimetics that can mimic both faces of an α-helix, as this may enhance the binding affinity of the synthetic ligand as well as improve its selectivity profile. Elaboration of previously-reported α-helix mimetic scaffolds has allowed for mimicry of both faces of the α-helix [19]. Novel and diverse amphipathic α-helix mimetic scaffolds would be welcomed to enhance the pool of potential leads for drug discovery.